I-alkyl z



United States Patent l-ALKYL 2,5-DIMETHYL PIPERAZINES Richard Baltzlyand Marion B. Sherwood, Westchester County, N. Y., assignors toBurroughs Wellcome & Co. g1. A.) Inc., Tuckahoe, N. Y., a corporation ofNew No Drawing. Application April 20, 1953, Serial No. 349,964

Claims priority, application Great Britain May 30, 1952 6 Claims. (Cl.260-268) This invention relates to a group of N-alkyl substituted2,5-dimethyl piperazines the members of which have unusual antibacterialand especially antifungal activity combined with relatively moderatetoxicity. In the investigation of antifungal compounds a number ofsubstituted piperazines have been studied. The known N-n-decyl andN-lauryl piperazines are fairly good fungicides as well as moderatelystrong disinfectants, the former being somewhat preferable. Activityfalls ofi with the lower members and also with the higher members of theseries. The corresponding derivaties of 2,5-dirnethylpiperazine whichare the subject of the present invention while somewhat similar arefound to possess definite advantages both as compared to the previouslyknown and mentioned N- alkyl piperazines and as compared to other knownfungicides.

One of the outstanding advantages of these l-alkyl-2,5-dimethylpiperazines, is that their fungicidal activity is onlyslightly diminished by the presence of protein material. For example,the concentration required to kill typical test organisms, such asTrichophyton interdigitale, Epidermatophyton floccosum and Moniliaalbzcans, is not much higher in the presence of blood serum than in itsabsence.

As compared to the corresponding l-alkylpiperazines, the compounds ofthis invention are consistently as active or more active as fungicides,are somewhat less toxic intraperitoneally (about 10%) and are markedlyless toxic when taken orally. For example, the oral LD-50 in mice of1-lauryl-2,S-dimethylpiperazine dihydrochloride is 1350 mg./kg. whilethat of l-laurylpiperazine dihydrochloride is 725 mg./kg. Such variationin oral toxicity, while of small concern for purely external applicationis of considerable interest if the fungicide is to be used againstmonilia infections of the throat and digestive tract, which infectionsare increasingly prominent of recent years apparently as a result of theuse of antibiotics in the treatment of bacterial infections.

The compounds of this invention may be represented by the formula:

wherein R is an alkyl group of 10 to 14 carbon atoms. It will beobserved that the methyl groups are in the transposition. Thesecompounds are capable of existence as d and l stereo-isomers but aresolution has not been accomplished up to the present. The bases areviscous oils or low melting solids, distillable in vacuo. Salts,especially di-hydrochlorides, are crystallizable from alcohol-ethermixtures or the like. Mono-hydrochlorides, which give approximatelyneutral solutions when dissolved in water, are isolable but are notreadily crystallized. On

'ice

the other hand, such neutral solutions are quite satisfactory fortherapeutic application.

The bases are conveniently prepared by refluxing 2,5- dimethylpiperazine with the appropriate alkyl halide in alcoholic solution. Inpractice we use about alcohol but other concentrations of alcohol orother solvents of similar dielectric constants are equivalent. It isdesirable that the concentration of water should be low enough toprevent formation of a separate layer by the alkyl halide and highenough to prevent excessive precipitation of salts. The proportions ofreactants are not critical but better utilization of alkyl halide isobtained if an excess of dimethyl piperazine is present. It is alsoadvantageous, though not necessary, to neutralize the dimethylpiperazine partially at the start so that mainly a monovalent cation {Hamug /NH) is present and to add small amounts of a base (sodiumbicarbonate) during the course of the reaction maintaining a pH of about8. In this manner the formation of N,N'-dialkyl piperazine is minimized.Below pH 6.5-7.0, however, the rate of alkylation is inconveniently slowwherefore it is not feasible to suppress dialkylation completely. Thecomplete buffering of this alkylation reaction would be desirable but isnot in fact convenient. Phosphates form insoluble precipitates with thestarting base; acetates tend to react with the alkyl halide which isusually the most expensive reagent. 'Probably the most economicalprocedure isto employ an excess (2,3-equiv.) of dimethylpiperazine. Theunreacted dimethylpiperazine can be recovered on a commercial scale,While N,N- dialkylated material is of no further value.

When the reaction is largely finished (which is shown by the pHremaining constant) most of the alcohol is boiled ofl, alkali is added,and the reaction mixture is partitioned between ether and water, theethereal layer being washed with water until the washings are nearlyneutral (pH 78). The ethereal layer is then extracted with dilutehydrochloric acid (ca; 1 N), which extracts first the salts of the mostsoluble base. By taking the acid in portions it is possible to get thebulk of the mono-N-alkyl base into aqueous solution as themonohydrochloride accompanied by very little of the N,N'- dialkylcompound. When solid appears in the separatory funnel it is advantageousto add an excess of hydrochloric acid whereby most of the N,N-dialkylpiperazine separates as the dihydrochloride and can be filtered off, theaqueous portion of the filtrate being added to the previous aqueousextracts. These combined extracts are then basified and the base istaken into ether, dried over potassium carbonate and distilled in vacuo.Yields average between 50 and 60%.

In addition to valuable activity against microorganisms the mono-N-alkylcompounds of this family are of value as intermediates since they can beconverted to urethanes, ureas, guanidines and the like.

EXAMPLE 1 2,5-dimethyl-1-n-decylpiperazine Thirty-four and one-half g.(0.3 mole) of 2,5-dimethyl piperazine was dissolved in 200 cc. ofethanol and 9 cc. (0.15 mole) of acetic acid was added. To this wasadded 60 g. (0.22 mole) of n-decyl iodide and the solution was refluxedtwenty-five hours. At the start the pH was about 9 and this had fallento 7 after 35 minutes. Sodium bicarbonate (12.5 g.=0.15 mole) was addedin portions over the next half-hour. At the end of the reflux periodmost of the alcohol Was boiled ofi. Water and sodium hydroxide solutionwas added to give a volume of about 200 cc. and the mixture wasthoroughly extracted with ether. The ethereal layer was washed withwater until the washings were neutral and extracted first with 80 cc. ofN hydrochloric acid, then with 40 cc. In this second extraction somesolid appeared. The ethereal layer was then shaken with 200 cc. of Nhydrochloric acid. The resultant suspension was filtered and washed withwater and ether. The solid (2,5-dimethyl-1,4-didecyl piperazinedihydrochloride) when dried weighed 20.5 g. (0.043 mole The ethereallayer on evaporation left 7.5 g. of neutral residue (in the main, decylacetate). The aqueous layers containing water-soluble salts of the baseswere united and basified. The oily base was taken into ether, dried onpotassium carbonate and distilled in vacuo. The 2,5-dirnethyl-l-n-decylpiperazine base boils at 115-122 at 1 mm. and forms a dihydrochloride(fiattish needles) that melts at 233-233.5 C. The yield was 27 g. (0.11mole) or 55% calculated on the decyl iodide used.

EXAMPLE 2 2,5-dimethyl-1-n-Imdecylpiperazine The procedure of Example 1was followed in the reaction of 47 g. (0.2 mole) of n-undecyl bromidewith 0.25 mole of 2,5-dimethylpiperazine. The2,5-dimethyll-n-undecylpiperazine obtained weighed 28.5 g. (0.105 moleor 52.5%), boiled at 135-136" C. at 1 mm. and formed a dihydrochloridemelting at 228. The yield of N,N'-diundecyl base was 0.03 mole and theneutral fraction weighed 11 g.

EXAMPLE 3 2,5-dimethyl-I-laurylpiperazine Thirty g. (0.26 mole) of2,5-dimethylpiperazine was reacted by the method of Example 1 with 3.5g. (0.014 mole) of lauryl bromide 26 g. (0.13 mole of lauryl chlorideand g. of sodium iodide). No acetic acid or sodium bicarbonate wasadded. The neutral fraction on working up weighed only 1 g. Theinsoluble dihydrochloride fraction (2,5-dimethyl-1,4-dilaurylpiperazinedihydrochloride) weighed 10.5 g. (0.02 mole) and the mono-N-alkylproduct, which boiled at 142-143 C. (at 1 mm.) weighed 24 g. (60%) basedon the alkyl halide used. The dihydrochloride forms platelets and meltsat 229-231 C.

EXAMPLE 4 1-tetradecyl-2,5-dimethylpiperazine Thirty-nine grams of2,5-dimethylpiperazine was disthe pH to 7).

solved in 300 cc. of ethanol and partly neutralized with 25 cc. ofconcentrated hydrochloric acid (bringing The solution was heated toreflux with stirring and g. of crude tetradecyliodide was admittedgradually through a dropping funnel at such a rate as to minimizeseparation of layers. Sodium bicarbonate was added at intervals to keepthe pH 7 to 7.5. The reaction time was about 20 hours after which thebulk of the alcohol was boiled off and the residual material was workedup as described in Example 1. There was ob tained 7 g. of neutralmaterial, 43 g. of 1,4-ditetradecyl- 2,5-dimethylpiperazinedihydrochloride and 42 g. of 1- tetradecyl-2,5 dimethylpiperazine basewhich boils at about at 1 mm. pressure. It forms a dihydrochloride thatmelts with decomposition at 234 C.

We claim:

1. Compounds of the formula wherein R is an alkyl group of from 10 to 14carbon atoms, which comprises reacting an appropriate alkyl halide withtrans 2,5-dimethyl piperazine.

References Cited in the file of this patent UNITED STATES PATENTS StoehrJuly 17, 1894 Buck et al. Feb. 11, 1947 Hultquist et al. July 24, l95l

1. COMPOUNDS OF THE FORMULA
 6. A METHOD OF FORMING COMPOUNDS OF THEFORMULA